Targeting of mutant p53-induced FoxM1 with thiostrepton induces cytotoxicity and enhances carboplatin sensitivity in cancer cells
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Xuan Zhang1,*, Lihua Cheng1,*, Kay Minn1,*, Rashna Madan2, Andrew K. Godwin2, Viji Shridhar3, Jeremy Chien1
1Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas, U.S.A
2Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, U.S.A
3Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, U.S.A
*These authors contributed equally to the study
Jeremy Chien, e-mail: [email protected]
Received: June 04, 2014 Accepted: September 18, 2014 Published: December 04, 2014
FoxM1 is an oncogenic Forkhead transcription factor that is overexpressed in ovarian cancer. However, the mechanisms by which FoxM1 is deregulated in ovarian cancer and the extent to which FoxM1 can be targeted in ovarian cancer have not been reported previously. In this study, we showed that MDM2 inhibitor Nutlin-3 upregulated p53 protein and downregulated FoxM1 expression in several cancer cell lines with wild type TP53 but not in cell lines with mutant TP53. FoxM1 downregulation was partially blocked by cycloheximide or actinomycin D, and pulse-chase studies indicate Nutlin-3 enhances FoxM1 mRNA decay. Knockdown of p53 using shRNAs abrogated the FoxM1 downregulation by Nutlin-3, indicating a p53-dependent mechanism. FoxM1 inhibitor, thiostrepton, induces apoptosis in cancer cell lines and enhances sensitivity to cisplatin in these cells. Thiostrepton downregulates FoxM1 expression in several cancer cell lines and enhances sensitivity to carboplatin in vivo. Finally, FoxM1 expression is elevated in nearly all (48/49) ovarian tumors, indicating that thiostrepton target gene is highly expressed in ovarian cancer. In summary, the present study provides novel evidence that both amorphic and neomorphic mutations in TP53 contribute to FoxM1 overexpression and that FoxM1 may be targeted for therapeutic benefits in cancers.
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